当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Dicaffeoyltartaric acid analogues inhibit human immunodeficiency virus type 1 (HIV-1) integrase and HIV-1 replication at nontoxic concentrations.

Dicaffeoyltartaric acid analogues inhibit human immunodeficiency virus type 1 (HIV-1) integrase and HIV-1 replication at nontoxic concentrations.

Abstract：

:The human immunodeficiency virus type 1 (HIV-1) is a major health problem worldwide. In this study, 17 analogues of L-chicoric acid, a potent inhibitor of HIV integrase, were studied. Of these analogues, five submicromolar inhibitors of integrase were discovered and 13 compounds with activity against integrase at less than 10 microM were identified. Six demonstrated greater than 10-fold selectivity for HIV replication over cellular toxicity. Ten analogues inhibited HIV replication at nontoxic concentrations. Alteration of the linkages between the two bis-catechol rings, including the use of amides, mixed amide esters, cholate, and alkyl bridges, was explored. Amides were as active as esters but were more toxic in tissue culture. Alkyl and cholate bridges were significantly less potent against HIV-1 integrase in vitro and were inactive against HIV-1 replication. Two amino acid derivates and one digalloylderivative of L-chicoric acid (L-CA) showed improved selectivity over L-CA against integration in cell culture. These data suggest that in addition to the bis-catechols and free carboxylic acid groups reported previously, polar linkages are important constituents for optimal activity against HIV-1 integrase and that new derivatives can be developed with increased specificity for integration over HIV entry in vivo.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Reinke RA,King PJ,Victoria JG,McDougall BR,Ma G,Mao Y,Reinecke MG,Robinson WE Jr

doi

10.1021/jm010359d

keywords:

subject

Has Abstract

pub_date

2002-08-15 00:00:00

pages

3669-83

issue

17

eissn

0022-2623

issn

1520-4804

pii

jm010359d

journal_volume

45

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Studies on anticoccidial agents. 10. Synthesis and anticoccidial activity of 5-nitronicotinamide and its analogues.

    abstract：:5-Nitronicotinamide (1) was prepared from 5-bromonicotinoyl chloride by treatment with ammonia and then oxidation with fuming H2SO4 and 30% H202. 2-Cholor-, 2-alkoxy-2-benzyloxy,2-phenoxy-,2-alkylamino-, and 2-benzylamino-5-nitronicatinamides were also prepared via 2-chloro-3-cyano-5-nitropyridine. 2-Methyl-5-nitronic...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00211a027

    authors： Morisawa Y,Kataoka M,Kitano N,Matsuzawa T

    更新日期：1977-01-01 00:00:00

  • Synthesis of 5-substituted aminomethyluracils via the Mannich reaction.

    abstract：:An extension of the Mannich reaction, in which aminomethylation of the five position of uracil, is reported. Thus, primary and secondary alkylamines and primary aromatic amines containing ring-activating groups led to the title compounds 3-10. Compound 11 in which the aromatic ring contains the ring-deactivating nitro...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00224a032

    authors： Delia TJ,Scovill JP,Munslow WD,Burckhalter JH

    更新日期：1976-02-01 00:00:00

  • Synthesis and some pharmacological properties (4-beta-(2-thienyl)-L-alanine)oxytocin.

    abstract：:The synthesis and some biological activities of [4-beta-(2-thienyl)-L-alanine]oxytocin are reported. This analogue has been studied in an ongoing exploration of the biological effects of introducing amino acid residues with bulky hydrophobic side chains into the second corner position of the beta turn present in the c...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00199a022

    authors： Smith CW,Skala G,Walter R

    更新日期：1978-01-01 00:00:00

  • Improved scoring of ligand-protein interactions using OWFEG free energy grids.

    abstract：:A new approach to rapidly score protein-ligand interactions is tested on several protein-ligand systems. Results using this approach - the OWFEG free energy grid - are quite promising and are generally in better agreement with experiment (in some cases much better) than those obtained employing scoring techniques curr...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm000375v

    authors： Pearlman DA,Charifson PS

    更新日期：2001-02-15 00:00:00

  • An interdisciplinary approach to the design of new structures active at the beta-adrenergic receptor. Aliphatic oxime ether derivatives.

    abstract：:On the basis of results previously obtained from structural and theoretical studies on beta-adrenergic drugs, a series of aliphatic oxime ether derivatives (AOEDs) was synthesized. As expected, pharmacological in vitro tests showed that compounds examined exhibit a marked and competitive antagonism at beta-adrenocepto...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00380a001

    authors： Macchia B,Balsamo A,Lapucci A,Martinelli A,Macchia F,Breschi MC,Fantoni B,Martinotti E

    更新日期：1985-02-01 00:00:00

  • "Addition" and "Subtraction": Selectivity Design for Type II Maternal Embryonic Leucine Zipper Kinase Inhibitors.

    abstract：:While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improv...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.7b00033

    authors： Chen X,Giraldes J,Sprague ER,Shakya S,Chen Z,Wang Y,Joud C,Mathieu S,Chen CH,Straub C,Duca J,Hurov K,Yuan Y,Shao W,Touré BB

    更新日期：2017-03-09 00:00:00

  • A comparative molecular field analysis model for 6-arylpyrrolo[2,1-d] [1,5]benzothiazepines binding selectively to the mitochondrial benzodiazepine receptor.

    abstract：:A series of 42 6-arylpyrrolo[2,1-d][1,5]benzothiazepines, which we have recently described as selective ligands of the mitochondrial benzodiazepine receptor (MBR) (Fiorini I.; et al. J. Med. Chem. 1994, 37, 1427-1438), have been investigated using the comparative molecular field analysis (CoMFA) approach. The resultin...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00050a007

    authors： Greco G,Novellino E,Fiorini I,Nacci V,Campiani G,Ciani SM,Garofalo A,Bernasconi P,Mennini T

    更新日期：1994-11-25 00:00:00

  • Development of organometallic S6K1 inhibitors.

    abstract：:Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previous...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm5011868

    authors： Qin J,Rajaratnam R,Feng L,Salami J,Barber-Rotenberg JS,Domsic J,Reyes-Uribe P,Liu H,Dang W,Berger SL,Villanueva J,Meggers E,Marmorstein R

    更新日期：2015-01-08 00:00:00

  • Substituted trans-stilbenes, including analogues of the natural product resveratrol, inhibit the human tumor necrosis factor alpha-induced activation of transcription factor nuclear factor kappaB.

    abstract：:The transcription factor nuclear factor kappaB (NF-kappaB), which regulates expression of numerous antiinflammatory genes as well as genes that promote development of the prosurvival, antiapoptotic state is up-regulated in many cancer cells. The natural product resveratrol, a polyphenolic trans-stilbene, has numerous ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm060630x

    authors： Heynekamp JJ,Weber WM,Hunsaker LA,Gonzales AM,Orlando RA,Deck LM,Jagt DL

    更新日期：2006-11-30 00:00:00

  • Adenosine analogues as inhibitors of Trypanosoma brucei phosphoglycerate kinase: elucidation of a novel binding mode for a 2-amino-N(6)-substituted adenosine.

    abstract：:As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N(6)-, 2-amino-N(6)-, and N(2)-substituted adenosine analogues were synthesized and tested to establish structure-activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate ki...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm000287a

    authors： Bressi JC,Choe J,Hough MT,Buckner FS,Van Voorhis WC,Verlinde CL,Hol WG,Gelb MH

    更新日期：2000-11-02 00:00:00

  • 2-[(4-phenylpiperazin-1-yl)methyl]imidazo(di)azines as selective D4-ligands. Induction of penile erection by 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazo[1,2-a]pyridine (PIP3EA), a potent and selective D4 partial agonist.

    abstract：:A series of novel 2-[(4-phenylpiperazin-1-yl)methyl]imidazoazines and aza-analogues were prepared and screened at selected dopamine, serotonin, and adrenergic receptor subtypes. 2-Substituted imidazopyridines and pyridazines presented high affinities and selectivities for D4 dopamine receptors. Whereas functional expe...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm060166w

    authors： Enguehard-Gueiffier C,Hübner H,El Hakmaoui A,Allouchi H,Gmeiner P,Argiolas A,Melis MR,Gueiffier A

    更新日期：2006-06-29 00:00:00

  • Potent and selective fluoroketone inhibitors of group VIA calcium-independent phospholipase A2.

    abstract：:Group VIA calcium-independent phospholipase A(2) (GVIA iPLA(2)) has recently emerged as a novel pharmaceutical target. We have now explored the structure-activity relationship between fluoroketones and GVIA iPLA(2) inhibition. The presence of a naphthyl group proved to be of paramount importance. 1,1,1-Trifluoro-6-(na...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm901872v

    authors： Kokotos G,Hsu YH,Burke JE,Baskakis C,Kokotos CG,Magrioti V,Dennis EA

    更新日期：2010-05-13 00:00:00

  • Synthesis and carbonic anhydrase isoenzymes I, II, IX, and XII inhibitory effects of dimethoxybromophenol derivatives incorporating cyclopropane moieties.

    abstract：:Cyclopropylcarboxylic acids and esters and cyclopropylmethanols incorporating bromophenol moieties were investigated as inhibitors of the carbonic anhydrase enzyme (CA; EC 4.2.1.1). The cis- and trans-esters 5 and 6 were obtained from the reaction of 4-allyl-1,2-dimethoxybenzene (4) with ethyl diazoacetate, which afte...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm501573b

    authors： Boztaş M,Çetinkaya Y,Topal M,Gülçin İ,Menzek A,Şahin E,Tanc M,Supuran CT

    更新日期：2015-01-22 00:00:00

  • Identification of the Metabolic Profile of the α-Tubulin-Binding Natural Product (-)-Pironetin.

    abstract：:Pironetin, the only crystallographically confirmed natural product to target α-tubulin, displays potent cytotoxic activity against sensitive and resistant A2780 ovarian cancer cell lines but is only marginally active in vivo. We now report that pironetin has a short half-life (<7 min) in human liver microsomes, sugges...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b01774

    authors： Coulup SK,Huang DS,Wong HL,Georg GI

    更新日期：2019-02-14 00:00:00

  • SAR analysis of adenosine diphosphate (hydroxymethyl)pyrrolidinediol inhibition of poly(ADP-ribose) glycohydrolase.

    abstract：:Polyadenosine diphosphoribose glycohydrolase (PARG) catalyzes the intracellular hydrolysis of adenosine diphosphoribose polymers. Because structure-activity data are lacking for PARG, the specific inhibitor adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD) was utilized to determine the effects of structur...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm020541u

    authors： Koh DW,Coyle DL,Mehta N,Ramsinghani S,Kim H,Slama JT,Jacobson MK

    更新日期：2003-09-25 00:00:00

  • Protoberberine alkaloids as antimalarials.

    abstract：:The protoberberine alkaloids berberine (1), palmatine (2), jatrorrhizine (3), and several berberine derivatives (4-10) were tested for antimalarial activity in vitro against Plasmodium falciparum and in vivo against Plasmodium berghei. The berberine derivatives 4-10 were designed and synthesized to maximize structural...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00401a006

    authors： Vennerstrom JL,Klayman DL

    更新日期：1988-06-01 00:00:00

  • N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (6b): a novel anticancer glycyrrhetinic acid derivative that targets the proteasome and displays anti-kinase activity.

    abstract：:18-β-Glycyrrhetinic acid (GA; 1) and many of its derivatives are cytotoxic in cancer cells. The current study aims to characterize the anticancer effects of 17 novel 1 derivatives. On the basis of these studies, N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (6b) appeared to be the most potent...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm200285z

    authors： Lallemand B,Chaix F,Bury M,Bruyère C,Ghostin J,Becker JP,Delporte C,Gelbcke M,Mathieu V,Dubois J,Prévost M,Jabin I,Kiss R

    更新日期：2011-10-13 00:00:00

  • Discovery of 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d]pyrimidine, an orally active, non-nucleoside adenosine kinase inhibitor..

    abstract：:Adenosine (ADO) is an endogenous homeostatic inhibitory neuromodulator that reduces cellular excitability at sites of tissue injury and inflammation. Inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO, selectively increases ADO concentrations at sites of tissue trauma and enhances the analgesic ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm000314x

    authors： Lee CH,Jiang M,Cowart M,Gfesser G,Perner R,Kim KH,Gu YG,Williams M,Jarvis MF,Kowaluk EA,Stewart AO,Bhagwat SS

    更新日期：2001-06-21 00:00:00

  • Conformational effects on the activity of drugs. 7. Synthesis and pharmacological properties of 2-(p-nitrophenyl)-substituted morpholines.

    abstract：:A series of 1-(p-nitrophenyl)-2-aminoethanol derivatives and their morpholine analogues have been synthesized and pharmacologically investigated in order to confirm some pharmacological observations made with the N-isopropyl-substituted compounds. In agreement with the previously obtained results, the weak alpha-adren...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00192a023

    authors： Balsamo A,Crotti P,Lapucci A,Macchia B,Macchia F,Del Tacca M,Mazzanti L,Ceserani R

    更新日期：1979-06-01 00:00:00

  • High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT).

    abstract：:Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that methylates nicotinamide (NAM) using cofactor S-adenosylmethionine (SAM). NNMT overexpression has been linked to diabetes, obesity, and various cancers. In this work, structure-based rational design led to the development of potent and selective alkynyl...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.9b01238

    authors： Policarpo RL,Decultot L,May E,Kuzmič P,Carlson S,Huang D,Chu V,Wright BA,Dhakshinamoorthy S,Kannt A,Rani S,Dittakavi S,Panarese JD,Gaudet R,Shair MD

    更新日期：2019-11-14 00:00:00

  • Structural Simplification of a Tetrahydroquinoline-Core Peptidomimetic μ-Opioid Receptor (MOR) Agonist/δ-Opioid Receptor (DOR) Antagonist Produces Improved Metabolic Stability.

    abstract：:We have previously reported a series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist ligands to serve as potential nonaddictive opioid analgesics. These ligands have been shown to be active in vivo, do not manifest withdrawal syndromes or reward behavior in conditioned-place preference assays in ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.9b00219

    authors： Henry SP,Fernandez TJ,Anand JP,Griggs NW,Traynor JR,Mosberg HI

    更新日期：2019-04-25 00:00:00

  • Conformational studies on a diastereoisomeric pair of tricyclic nonclassical cannabinoids by NMR spectroscopy and computer molecular modeling.

    abstract：:Among the nonclassical cannabinoids, CP-55,244 (4), which incorporates an axial 14 beta-hydroxymethyl group, is pharmacologically 30 times more potent than its prototype CP-47,497 (2) and 300 times more potent than delta 9-THC (1). It has a high degree of stereoselectivity (about 120:1) with respect to its diastereois...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm960410r

    authors： Xie XQ,Pavlopoulos S,DiMeglio CM,Makriyannis A

    更新日期：1998-01-15 00:00:00

  • Radiosynthesis of sigma receptor ligands for positron emission tomography: 11C- and 18F-labeled guanidines.

    abstract：:A series of analogues of the potent and selective sigma receptor ligand 1,3-ditolylguanidine (DTG) were synthesized and demonstrated to have high affinity for the sigma receptor as measured by in vitro [3H]DTG displacement studies using guinea pig brain tissue. Three of these 1-aryl-3-(1-adamantyl)guanidines were radi...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00110a017

    authors： Wilson AA,Dannals RF,Ravert HT,Sonders MS,Weber E,Wagner HN Jr

    更新日期：1991-06-01 00:00:00

  • Identification of Inhibitors for the DEDDh Family of Exonucleases and a Unique Inhibition Mechanism by Crystal Structure Analysis of CRN-4 Bound with 2-Morpholin-4-ylethanesulfonate (MES).

    abstract：:The DEDDh family of exonucleases plays essential roles in DNA and RNA metabolism in all kingdoms of life. Several viral and human DEDDh exonucleases can serve as antiviral drug targets due to their critical roles in virus replication. Here using RNase T and CRN-4 as the model systems, we identify potential inhibitors ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b00794

    authors： Huang KW,Hsu KC,Chu LY,Yang JM,Yuan HS,Hsiao YY

    更新日期：2016-09-08 00:00:00

  • Novel Oxazolidinone-Based Peroxisome Proliferator Activated Receptor Agonists: Molecular Modeling, Synthesis, and Biological Evaluation.

    abstract：:A series of new peroxisome proliferator activated receptors (PPARs) chiral ligands have been designed following the accepted three-module structure comprising a polar head, linker, and hydrophobic tail. The majority of the ligands incorporate the oxazolidinone moiety as a novel polar head, and the nature of the hydrop...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.5b00849

    authors： Fresno N,Macías-González M,Torres-Zaguirre A,Romero-Cuevas M,Sanz-Camacho P,Elguero J,Pavón FJ,Rodríguez de Fonseca F,Goya P,Pérez-Fernández R

    更新日期：2015-08-27 00:00:00

  • Combining pharmacophore search, automated docking, and molecular dynamics simulations as a novel strategy for flexible docking. Proof of concept: docking of arginine-glycine-aspartic acid-like compounds into the alphavbeta3 binding site.

    abstract：:A novel and highly efficient flexible docking approach is presented where the conformations (internal degrees of freedom) and orientations (external degrees of freedom) of the ligands are successively considered. This hybrid method takes advantage of the synergistic effects of structure-based and ligand-based drug des...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0311386

    authors： Moitessier N,Henry C,Maigret B,Chapleur Y

    更新日期：2004-08-12 00:00:00

  • EC144 is a potent inhibitor of the heat shock protein 90.

    abstract：:Alkyne 40, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpent-4-yn-2-ol (EC144), is a second generation inhibitor of heat shock protein 90 (Hsp90) and is substantially more potent in vitro and in vivo than the first generation inhibitor 14 (BIIB021) that co...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm300810x

    authors： Shi J,Van de Water R,Hong K,Lamer RB,Weichert KW,Sandoval CM,Kasibhatla SR,Boehm MF,Chao J,Lundgren K,Timple N,Lough R,Ibanez G,Boykin C,Burrows FJ,Kehry MR,Yun TJ,Harning EK,Ambrose C,Thompson J,Bixler SA,Dunah

    更新日期：2012-09-13 00:00:00

  • Structural studies on bioactive compounds. 39. Biological consequences of the structural modification of DHFR-inhibitory 2,4-diamino-6-(4-substituted benzylamino-3-nitrophenyl)-6-ethylpyrimidines ('benzoprims').

    abstract：:Benzimidazole-N-oxide modifications of potent lipophilic dihydrofolate reductase (DHFR) inhibitors (e.g., methylbenzoprim 1 and dichlorobenzoprim 2) have been prepared by base-promoted cyclization of the nitrophenylbenzylamino groups to explore the possibility that abrogation of DHFR-inhibitory activity might reveal c...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm040785+

    authors： Richardson ML,Croughton KA,Matthews CS,Stevens MF

    更新日期：2004-07-29 00:00:00

  • Optimization of the indenone ring of indenoisoquinoline topoisomerase I inhibitors.

    abstract：:Two series of indenoisoquinoline topoisomerase I inhibitors have been prepared to investigate optimal substituents on the indenone ring at the 9-position. The more exhaustive series was prepared using a nitrated isoquinoline ring that has been previously demonstrated to enhance biological activity. After preliminary b...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm070307+

    authors： Morrell A,Placzek M,Parmley S,Grella B,Antony S,Pommier Y,Cushman M

    更新日期：2007-09-06 00:00:00

  • Phototoxicity of chlorpromazine.

    abstract：:The constitution of chlorpromazine has been studied in the context of its phototoxicity. Electron transfer from the side chain to the aromatic nucleus of the drug contributes to its instability to light. Even without the side chain, however, chlorophenothiazines appear to be very photolabile, so that it is unlikely th...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00188a016

    authors： Bunce NJ,Kumar Y,Ravanal L

    更新日期：1979-02-01 00:00:00